Method for preventing the onset of asthma

ABSTRACT

The present invention relates to a method for preventing the onset of asthma which comprises administering to a patient a therapeutically effective amount of cetirizine, an individual optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0001] The present invention relates to a method for preventing theonset of asthma with cetirizine, an individual optical isomer thereof ora pharmaceutically acceptable salt thereof.

[0002] The prevalence of asthma, atopic dermatitis and hay fever hasincreased over the last three decades in many countries (ISAAC, Lancet1998:351:1225-32) and the health and economic burden of these diseasesare considerable. So far, no intervention has been shown to alter thenatural history of asthma and hay fever. It is known that exposure tohigh levels of allergen in early life is a major trigger for asthma (U.WAHN et al., Pediatr. Allergy Immunol. 1997:8 (10 suppl): 16-20).Attempts at prevention of allergen avoidance have produced conflictingresults with no benefit at all (R. S. ZEIGER et al., Pediatr. AllergyImmunol. 1992:3:110-27), only transient effects or, in the case of onestudy, a long lasting effect (U. M. SAARINEN et al., Lancet 1995:346:1065-69; D. W. HIDE et al., Allergy:51(2): 89-93). There is also astrong association between atopic dermatitis and the subsequentdevelopment of asthma. Around 40% of infants with atopic dermatitis inearly infancy will develop asthma at the age of 3 to 4 years.

[0003] Clearly, the prevalence of asthma and its consequences call foreffective methods of preventing asthma.

[0004] There are two studies reporting the prophylactic use of ketotifenfor the prevention of asthma in preasthmatic children with non specificelevated IgE level (Y. Iikura et al., Ann. Allergy 1992: 68: 233-36; G.J. BUSTOS et al., Clin. Exp. Allergy 1995: 25(6):568-73). However, theuse of ketotifen in infants and very young children is often associatedwith side-effects such as drowsiness or nervous excitation.

[0005] Therefore, it remains desirable to find other therapeutic methodsand pharmaceutical compositions for preventing the onset of asthma, inparticular in infants or young children.

[0006] The first purpose of the invention concerns the primaryprevention of asthma: prevention of sensitisation of infants at risk ofdeveloping asthma diseases.

[0007] The second purpose of the invention is the prevention of allergicasthma in infants at high risk and evidence of aeroallergen (grasspollen or house dust mite) sensitization.

[0008] The present invention is based on the unexpected recognition thatadministration of pharmaceutical compositions comprising cetirizine, anindividual optical isomer thereof or a pharmaceutically acceptable saltthereof to infants prevents the onset of asthma.

[0009] The present invention encompasses a method for preventing orretarding the onset of asthma which comprises administering to a patienta therapeutically effective amount of cetirizine, an individual opticalisomer thereof or a pharmaceutically acceptable salt thereof.

[0010] The present invention also encompasses the use of cetirizine, anindividual optical isomer thereof or a pharmaceutically acceptable saltthereof for the preparation of a medicament intended for the preventionof asthma.

[0011] The present invention also concerns the use of cetirizineintended for preventing the onset of asthma in a patient, the saidmedicament being administered to the patient to the patient prior theonset of asthma (e.g. before any biological or clinical symptoms ofallergic disease occurs (primary prevention) or after biological signsof sensitization to allergens but before the onset of symptoms of asthma(secondary prevention)).

[0012] The present invention also concerns the use of cetirizine, anindividual optical isomer thereof or a pharmaceutically acceptable saltthereof for the preparation of a medicament intended for preventing theonset of asthma in a patient, the said medicament being administered tothe patient prophylactically prior to the onset of asthma.

[0013] The present invention also concerns the use of cetirizine, anindividual optical isomer thereof or a pharmaceutically acceptable saltthereof for the preparation of a medicament intended for preventing thesensitisation of patient at risk of developing asthma diseases.

[0014] The term cetirizine as used herein refers to2-[2-[4-(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid.Processes for preparing cetirizine, an individual optical isomer thereofor a pharmaceutically acceptable salt thereof have been described inEuropean Patent 0 058 146, Great Britain Patent 2.225.320, Great BritainPatent 2.225.321, U.S. Pat. No. 5,478,941, European Patent application 0601 028, European Patent Application 0 801 064 and International PatentApplication WO 97/37.982.

[0015] The term “pharmaceutically acceptable salts” as used hereinrefers not only to addition salts with pharmaceutically acceptablenon-toxic organic and inorganic acids, such as acetic, citric, maleic,succinic, ascorbic, hydrochloric, hydrobromic, sulfuric, and phosphoricacids and the like, but also its metal salts (for example sodium orpotassium salts) or ammonium salts, the amine salts and the aminoacidsalts. The best results have been obtained with cetirizinedihydrochloride.

[0016] The term “individual optical isomer” as used herein means thelevorotatory and the dextrorotatary enantiomers of cetirizine. Moreprecisely, it means that the active substance comprises at least 90% byweight, preferably at least 95% by weight, of one individual opticalisomer of cetirizine and at most 10% by weight, preferably at most 5% byweight, of the other individual optical isomer of cetirizine. Eachindividual optical isomer may be obtained by conventional means, i.e.,resolution from the corresponding racemic mixture or by asymmetricsynthesis.

[0017] By patient, we understand infants and children, in particularyoung children. Generally, the patients are infants or children aged 3months to 10 years, preferably aged 6 months to 5 years, and morepreferably 10 months to 5 years. The best results have been obtainedwith patients aged 1 to 4 years.

[0018] According to the invention, the patient is not affected by asthmadisease. Preferably, the patient has never been affected by asthmadiseases.

[0019] Asthma is an inflammatory disease. Symptoms are presence of coughand/or wheezing, in particular recurrent cough and/or wheezing, and morespecifically allergic wheezing or nocturnal cough with sleep disturbancelasting for at least 2 consecutive nights. Asthma can be defined as atleast 2 separate episodes of nocturnal cough with sleep disturbanceslasting for 2 consecutive nights or 2 separate episodes of wheezing.Asthma attack is defined as any episode of nocturnal cough with sleepdisturbances lasting for 2 consecutive nights or any episode of wheezingrequiring treatment; the second episode of wheezing or nocturnal coughis to be considered as the first asthma attack.

[0020] A therapeutically effective amount of cetirizine, an individualoptical isomer thereof or a pharmaceutically acceptable salt thereof isused to alleviate the effects of an asthma attack or to prevent orretard onset of an asthma attack. The dosage depends essentially on thespecific method of administration and on the purpose of the prophylaxis.The size of the individual doses and the administration program can bestbe determined based on an individual assessment of the relevant case.The methods required to determine the relevant factors are familiar tothe expert.

[0021] A preferred daily dosage provides from about 0.0005 mg to about 2mg of cetirizine, an individual optical isomer thereof or apharmaceutically acceptable salt thereof, per kg of body weight perpatient. A particularly preferred daily dosage is from about 0.005 toabout 2 mg per kg of body weight per patient. The best results have beenobtained with a daily dosage from about 0.05 to 1 mg per kg of bodyweight per patient. The dosage may be administered once per day oftreatment, or divided into smaller dosages, for examples 1 to 4 times aday, and preferably 1 to 3 times a day, and administrated over about a24 hours time period to reach a total given dosage. Best results havebeen obtained with an administration twice a day; the pharmaceuticalcompositions of the invention are taken in two equal doses per day. Theexact dosages in which the compositions are administrated can varyaccording to the type of use, the mode of use, the requirements of thepatient, as determined by a skilled practitioner. The exact dosage for apatient may be specifically adapted by a skilled person in view of theseverity of the condition, the specific formulation used, and otherdrugs which may be involved.

[0022] Pharmaceutical compositions used according to the presentinvention may be administered by any conventional means. The routes ofadministration include intradermal, transdermal, slow releaseadministration, intramuscular, oral and intranasal routes. Any otherconvenient route of administration can be used, for example absorptionthrough epithelial or mucocutaneous linings.

[0023] The pharmaceutical forms according to the present invention maybe prepared according to conventional methods used by pharmacists. Theforms can be administered together with other components or biologicalyactive agents, pharmaceutically acceptable surfactants, excipients,carriers, diluents and vehicles.

[0024] The pharmaceutical compositions of the invention include anyconventional therapeutical inert carrier. The pharmaceuticalcompositions can contain inert as well as pharmacodynamically activeadditives. Liquid compositions can for example take the form of asterile solution which is miscible with water. Furthermore, substancesconventionally used as preserving, stabilizing, moisture-retaining, andemulsifying agents as well as substances such as salts for varying theosmotic pressure, substances for varying pH such as buffers, and otheradditives can also be present. If desired an antioxidant can be includedin the pharmaceutical compositions. Pharmaceutical acceptable excipientsor carriers for compositions include saline, buffered saline, dextroseor water. Compositions may also comprise specific stabilizing agentssuch as sugars, including mannose and mannitol. Carrier substances anddiluents can be organic or inorganic substances, for example water,gelatine, lactose, starch, magnesium stearate, talc, gum arabic,polyalkylene glycol and the like. A prerequisite is that all adjuvantsand substances used in the manufacture of the pharmaceuticalcompositions are nontoxic.

[0025] Pharmaceutical compositions can be administered by sprayinhalation. Any conventional pharmaceutical composition for sprayinhalation administration may be used. Another preferred mode ofadministration is by aerosol.

[0026] The pharmaceutical composition of the invention can also beformulated for topical application. The composition for topicalapplication can be in the form of an aqueous solution, lotion or jelly,an oily solution or suspension or a fatty or emulsion ointment.

[0027] The pharmaceutical composition of the invention can also be usedfor slow prolonged release with a transdermal therapeutic system inpolymer matrix or with an appropriate formulation for oral slow release.

[0028] The pharmaceutical compositions according to the presentinvention may also be administered orally or rectally. They may also beadministered by nasal instillation (aerosols) or in the form of unguentsor creams. The pharmaceutical compositions which can be used for oraladministration may be solid or liquid, for example, in the form ofuncoated or coated tablets, pills, dragees, gelatine capsules,solutions, syrups and the like. For administration by the rectal route,the compositions containing the compounds of the present invention aregenerally used in the form of suppositories.

[0029] The pharmaceutical forms, such as tablets, drops, suppositoriesand the like, are prepared by conventional pharmaceutical methods. Thecompounds of the present invention are mixed with a solid or liquid,non-toxic and pharmaceutically acceptable carrier and possibly alsomixed with a dispersing agent, a disintegration agent, a stabilizingagent and the like. If appropriate, it is also possible to addpreservations, sweeteners, coloring agents and the like.

[0030] Preferably, the pharmaceutical compositions of the invention isadministered in traditional form for oral administration, as film coatedtablets, lozenges, dragees, and oral liquid preparation such as syrup.

[0031] Best results have been obtained with an oral dosage form, inparticular liquid formulations such as syrup. For example, patients canreceive 2 doses of 0.25 mg/kg (total daily dose: 0.50 mg/kg/day) of anoral solution of cetirizine 10 mg/ml per day; one ml of the solutioncontains 20 drops and one drop of cetirizine solution contains 0.5 mg.

[0032] As an Example of a composition according to the presentinvention, the following formulation of a syrup is preferred: cetirizinedihydrochloride, methyl- and propylparaben, saccharinum, and purifiedwater.

[0033] As an Example of a composition according to the presentinvention, the following formulation of a film coated tablet ispreferred: cetirizine dihydrochloride, magnesium stearate, cellulose,lactose and silicon dioxide.

[0034] Pharmaceutical compositions of the invention are usefulprophylactically. These compositions can alleviate the effects of theasthma attack. These compositions can delay or prevent onset of asthma.

[0035] Pharmaceutical compositions of the invention allow to decreasethe need of corticoid compounds, such as corticosteroids, needed for anyallergic disease.

[0036] Another advantage of the invention is the ability of the processto prevent onset of asthmatic attacks and to reduce symptoms subsequentto its initiation. The method of the invention is believed particularlysuited to use in patients susceptible to pulmonary inflammation.

[0037] Another advantage of the invention takes place in the fact thatan early treatment with cetirizine dihydrochloride (initiated between 1and 2 years of age) halved the number of children developing asthma,when they were suffering from atopic dermatitis and were sensitized(raised specific IgE antibody levels≧0.35 kUA/l) to grass pollen orhouse dust mite.

[0038] The invention allow to decrease the relative risk for developingasthma, in children sensitized to egg, milk, cat, house dust mite andgrass pollen.

[0039] The pharmaceutical composition of the invention is used toprevent the onset of asthma in patients considered to be at high risk ofdeveloping the disease. These patients have been described aspreasthmatic but are still asthma free.

[0040]FIGS. 1 and 2 represent the occurrence of asthma by treatment inpatients sensitised respectively to house dust mite at baseline for FIG.1 (Cetirizine (N=36) and Placebo (N=34)) and to grass pollen at baselinefor FIG. 2 (Cetirizine (N=56) and Placebo (N=68)). The abscissarepresents the time (months) and the ordinate represents the probabilityfor developing asthma. The curve with -.- corresponds to the placebo,and the curve with -♦- corresponds to cetirizine dihydrochloridetreatment.

[0041] The invention is further defined by reference to the followingexample.

EXAMPLE

[0042] The aim of the study relative to the clinical effect ofcetirizine dihydrochloride was to establish on the intention to treat(ITT population) whether an 18 month cetirizine dihydrochloridetreatment can prevent the onset of asthma in young children with atopicdermatitis, when compared to placebo. Subgroups based on the baselinestatus of biological markers as well as specific asthmatic patients(i.e. wheezers only; asthma onset date at least 3 months afterinclusion) were foreseen as well. It was considered that a 30% reductionof the incidence of asthma is clinically relevant. Secondary parametersof efficacy included the severity of asthma and atopic dermatitis. Thesafety of this long-term treatment with cetirizine dihydrochloride ininfants has also been evaluated.

[0043] The target population of this example consisted of infants aged 1to 2 years with active symptoms of atopic dermatitis for at least onemonth before enrollment. All the infants had to have at least one parentor sibling with a history of atopic disease (atopic dermatitis, allergicrhinitis or asthma). Excluded were infants with asthma, or with ahistory of any episodes of wheezing or nocturnal cough as well as anycondition likely to obscure the diagnosis of asthma (Guidelines for thediagnosis and management of asthma. National Asthma Education andPrevention Program. Expert Panel Report II. National Institute of Healthpublication 97-4051; International Report. International consensusreport on diagnosis and treatment of asthma. National Heart, Lung andBlood Institute. National Institute of Health publication 92-3091).

[0044] The study was a prospective, randomized, double blind, parallelgroup, and placebo-controlled study with cetirizine dihydrochloride.

[0045] The severity of atopic dermatitis was rated with the atopicdermatitis scale SCORAD (Consensus Report of the European Task Force onAtopic Dermatitis. Severity Scoring of Atopic Dermatitis: the SCORADIndex. Dermatology 1993; 186: 23-31.).

[0046] Study treatment lasted for 18 months. After the treatment period,patients entered a long-term follow-up period.

[0047] The primary end-point for efficacy was the onset of asthma,defined as 3 episodes of nocturnal cough with sleep disturbances orwheezing, separated by at least 7 days, in a clinical setting whereasthma is likely and conditions other than allergy have been excluded.

[0048] Secondary parameters of efficacy included the severity of asthma,consumption of concomitant medications and the severity of symptomsrelated to the atopic dermatitis evaluated according to the SCORADscore.

[0049] Serum total and specific (grass pollen, cow's milk, egg, housedust mites and cat dander) IgE antibody levels were determined using thePharmacia CAP® system (Pharmacia & Upjohn, Uppsala, Sweden). Theseanalyses were made at baseline, and after 3, 12 and 18 months oftreatment by a central laboratory (Institut Pasteur—Lille, France)according to instructions of the manufacturer and routine clinicallaboratory performances.

[0050] At each of the nine visits, the atopy status, any concurrentillnesses, concomitant medications and procedures were recorded.Patients underwent a physical examination, including the measurement ofvital signs.

[0051] Adverse events were recorded by the parents on diary cards anddiscussed with the investigator at each visit. Serious adverse eventshad to be reported immediately.

[0052] Oral solutions of cetirizine dihydrochloride (10 mg/ml) andmatching placebo, similar in appearance and taste were used. Therecommended study dosage was 0.25 mg cetirizine/kg b.i.d. (b.i.d.=“bisin die”, 2 times a day).

[0053] Sample size was based on an expected cumulative incidence ofasthma in 40% of children in the placebo group after 18 months oftreatment. A decrease of 30% of the incidence was considered asclinically relevant.

[0054] The baseline characteristics of the two treatment groups,including the mean SCORAD values, family history of atopy andenvironmental factors were comparable.

[0055] Infants in the placebo group, with raised baseline levels ofserum total IgE (≧30 kU/l) or specific IgE antibodies (≧0.35 kUA/l) hadan increased relative risk of developing asthma (Table 1). This increasewas observed for all measured IgE antibodies and was significant fortotal IgE, grass pollen, house dust mite and cat dander allergens.

[0056] The present study is the first to show that sensitization tograss pollen in such young infants is a powerful predictor of futureonset of asthma.

[0057] Analysis of the subgroups based on immunological parametersshowed statistically significant differences of high clinical relevance.(Table 2—FIGS. 1 and 2).

[0058] Infants receiving cetirizine dihydrochloride, who began the studywith raised baseline levels of total IgE (≧30 kU/l) or specific IgEantibodies (≧0.35 kUA/l) had a reduced risk of developing asthmacompared with those infants with raised baseline IgE antibodies, whoreceived placebo.

[0059] This reduction was observed for all measured IgE antibodies andwas significant for grass pollen (p=0.002) and house dust mite(p=0.005), either alone or combined (FIGS. 1 and 2).

[0060] There were no significant differences in the adverse event (AE)profiles between groups except for urticaria (16.1% versus 5.8%,p<0.001) which was less frequent in the cetirizine group.

[0061] The study shows that early treatment with cetirizinedihydrochloride (initiated between 1 and 2 years of age) halved thenumber of children developing asthma, when they were suffering fromatopic dermatitis and were sensitized (raised specific IgE antibodylevels≧0.35 kUA/l) to grass pollen or house dust mite.

[0062] Inclusion criteria were pragmatic and based on simple clinicalassessment: atopic dermatitis was defined using well-published standardcriteria (T. L. DIEPGEN et al., J Clin Epidemiol 1996; 49(9): 1031-38.;H. A. SAMPSON, Ann Allergy 1992;69(6). 469-79.).

[0063] Cetirizine dihydrochloride significantly reduced the risk ofsubsequent asthma in infants with the strongest predictors fordeveloping it. For these infants who were sensitized to grass pollen orhouse dust mite, the relative risk of subsequent asthma was reduced to0.5 and 0.6 respectively.

[0064] While it is clear that antihistamines do not play a major role inthe treatment of asthma, cetirizine has the potential to prevent theonset of asthma. This hypothesis is substantiated by the presentfindings. Allergic asthma has been prevented in infants at high risk andevidence of aeroallergen (grass pollen or house dust mite)sensitization. As early house dust mite sensitivity in childhood asthmais associated with persistent symptoms in long-term follow-up (R. SPORIKet al., N Eng J Med 1990; 323(8):502-07.), it is likely that thisintervention will be highly cost-effective.

[0065] This large trial in infants has shown that cetirizinedihydrochloride is a safe product. This double-blind trial of the use ofcetirizine dihydrochloride in infants with atopic dermatitis shows thatit successfully prevents asthma in infants with evidence of sensitivityto either grass pollen or house dust mite.

1. Use of cetirizine, an individual optical isomer thereof or apharmaceutically acceptable salt thereof for the preparation of amedicament intended for preventing the onset of asthma in a patient. 2.Use of cetirizine, an individual optical isomer thereof or apharmaceutically acceptable salt thereof for the preparation of amedicament intended for preventing the onset of asthma in a patient, thesaid medicament being administered to the patient prophylactically priorto the onset of asthma.
 3. Use of cetirizine, an individual opticalisomer thereof or a pharmaceutically acceptable salt thereof for thepreparation of a medicament intended for preventing the sensitisation ofpatient at risk of developing asthma diseases.
 4. Use according to claim1, 2 or 3, wherein the salt is the cetirizine dihydrochloride.
 5. Useaccording to claim 1, 2, 3 or 4, wherein the patient is an infant or achild.
 6. Use according to claim 5, wherein the patient is aged 1 to 4years.
 7. Use according to any one of claims 1 to 6, which comprisesadministering a daily dosage from about 0.0005 mg to about 2 mg of saidcetirizine, said individual optical isomer thereof or saidpharmaceutically acceptable salt thereof, per kg of body weight perpatient.
 8. Use according to claim 7, which comprises administering adaily dosage from about 0.05 mg to about 1 mg per kg of body weight perpatient.
 9. Use according to any one of claims 1 to 8, which comprisesadministration 1 to 3 times a day.
 10. Use according to any one ofclaims 1 to 10, wherein said cetirizine, said individual optical isomerthereof or said pharmaceutically acceptable salt thereof is administeredorally.
 11. A method for preventing the onset of asthma which comprisesadministering to a patient a therapeutically effective amount ofcetirizine, an individual optical isomer thereof or a pharmaceuticallyacceptable salt thereof. TABLE 1 Occurrence of Asthma by Baseline AtopicCharacteristics Placebo ITT Population (n = 397) RR for developingasthma in presence of elevated Log-Rank Normal Elevated marker Test (%)(%) [95% CI] p value Total IgE (PRIST)* (33.5) (43.6) 1.3 0.027 [1.0;1.7] IgE Grass pollen (GX1)* (35.0) (58.8) 1.7 <0.001 [1.2; 2.3] IgE HDM(D1)* (34.7) (51.5) 1.5 0.005 [1.1; 2.0] IgE Cat dander (E1)* (33.2)(47.1) 1.4. 0.032 [1.0; 1.9] IgE Egg (F1)* (30.7) (39.3) 1.3 0.152 [0.9;1.8] IgE Milk (F2)* (36.0) (40.9) 1.1 0.250 [0.9; 1.5] IgE HDM + GrassPollen (32.9) (53.7) 1.6 <0.001 [1.2; 2.1] Eosinophil count (34.9)(47.6) 1.4 0.066 [1.0; 1.9]

TABLE 2 Occurrence of Asthma by Treatment in the ITT population RR fordeveloping asthma when cetirizine Log-Rank Placebo Cetirizine treatedTest (%) (%) [95% CI] p value ITT population (38.0) (37.7) [0.8; 1.2]0.973 Subgroups with elevated IgE or eosinophils at baseline Total IgE(PRIST)* (43.6) (38.1) 0.9 0.391 [0.7; 1.1] IgE Grass pollen (GX1)*(58.8) (27.8) 0.5 0.002 [0.3; 0.91] IgE HDM (D1)* (51.5) (28.6) 0.60.005 [0.3; 0.91] IgE Cat dander (E1)* (47.1) (40.6) 0.9 0.610 [0.6;1.3] IgE Egg (F1)* (39.3) (31.2) 0.8 0.292 [0.6; 1.1] IgE Milk (F2)*(40.9) (30.7) 0.7 0.140 [0.5; 1.0] IgE HDM + Grass pollen (53.7) (34.2)0.6 0.006 [0.4; 0.9] Eosinophil count (47.6) (42.7) 0.9 0.674 [0.6; 1.3]